title: Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions.
abstract: We aimed to explore the major active components in grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ) that are responsible for OATP2B1-mediated drug interactions, by means of in vitro studies using Xenopus oocytes expressing OATP2B1 with a typical OATP2B1 substrate, estrone-3-sulfate. All three juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with half-maximum inhibition (IC50 ) values of 0.222% (GFJ), 0.807% (OJ), and 2.27% (AJ). Eight major flavonoids (naringin, naringenin, hesperidin, hesperetin, phloridzin, phloretin, quercetin, and kaempferol) contained in the juices inhibited OATP2B1-mediated estrone-3-sulfate uptake with IC50 values of 4.63, 49.2, 1.92, 67.6, 23.2, 1.31, 9.47, and 21.3 μM, respectively. When the concentration-IC50 ratios ([C]/IC50 ) of these flavonoids in GFJ, OJ, and AJ were calculated, values of [C]/IC50 ≥ 100 were obtained for naringin in GFJ and hesperidin in OJ. No flavonoid in AJ showed a ratio higher than unity. However, significant inhibition of OATP2B1 was observed with a mixture of phloridzin, phloretin, hesperidin, and quercetin at the concentrations present in AJ. In conclusion, our results indicate that naringin and hesperidin are the major OATP2B1 inhibitors in GFJ and OJ, respectively, whereas a combination of multiple components appears to be responsible for OATP2B1 inhibition by AJ.
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Megumi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Takanori
authors.initials: T
authors.lastname: Mori
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001628:Beverages / Q000032:analysis*; D032083:Citrus paradisi / Q000737:chemistry*; D032084:Citrus sinensis / Q000737:chemistry*; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D018565:Food-Drug Interactions; D015870:Gene Expression; D007408:Intestinal Absorption / Q000187:drug effects; D027845:Malus / Q000737:chemistry*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: D005419:Flavonoids; D027361:Organic Anion Transporters; D004970:Estrone; C017296:estrone sulfate
keywords: OATP2B1; Organic anion-transporting polypeptide transporters; apple juice; flavonoid; food interactions; grapefruit juice; interaction; intestinal absorption; intestinal secretion/transport; orange juice